Significant association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese patients.

AIM: Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines). METHODS: A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome-wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. RESULTS: We found a significant association (p = 9.41 × 10-10 ) of rs146644517 (G > A) with Kampo product-related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI patients contained HLA-B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75-24.46; p = 2.98 × 10-6 , corrected p = 4.17 × 10-5 ), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA-B*35:01. CONCLUSIONS: HLA-B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo-induced DILI in the Japanese population.

Classification of circadian pain rhythms and pain characteristics in chronic pain patients: An observational study.

ABSTRACT: This study aimed to perform cluster analysis in patients with chronic pain to extract groups with similar circadian rhythms and compare neuropathic pain and psychological factors among these groups to identify differences in pain-related outcomes. A total of 63 community-dwellers with pain lasting at least 3 months and Numerical Rating Scale scores of ≥2 were recruited from 3 medical institutions. Their pain circadian rhythms were evaluated over 7 days by measuring pain intensity at 6-time points per day using a 10-cm visual analog scale. Cluster analysis was performed using 6 variables with standardized visual analog scale values at 6-time points for individual participants to extract groups with similar pain circadian rhythms. The results of the Neuropathic Pain Symptom Inventory and psychological evaluations in each group were compared using the Kruskal-Wallis test. The results revealed 3 clusters with different circadian rhythms of pain. The total and evoked pain subscale Neuropathic Pain Symptom Inventory scores differed among the 3 clusters. The results suggest that a thorough understanding of circadian pain rhythms in chronic pain patients may facilitate the performance of activities of daily living and physical exercise from the perspective of pain management.

Successful combination of endoscopic and laparoscopic removal of multiple ingested needles: A case report.

RATIONALE: Foreign body (FB) ingestion is a relatively common clinical situation in the emergency department. However, multiple sharply pointed foreign bodies located in different organs are rare conditions and no definite treatment guidelines has been established. PATIENT CONCERNS: A 31-year-old amateur magician visited the outpatient clinic with a chief complaint of epigastric discomfort. He might have accidentally swallowed some needles while practicing a magic trick 2 days before. DIAGNOSIS: Imaging tests revealed 1 needle was stuck in the left liver lobe through the stomach wall, 1 was in the third portion of the duodenum, 3 were in the ascending colon, and 2 were in the transverse colon. INTERVENTIONS: A needle in the duodenum and 5 in the colon were removed by endoscopy. The needle stuck in the liver from the stomach was not visible inside the stomach and was successfully removed by laparoscopy a few days later. OUTCOMES: The patient was able to tolerate an oral diet and was discharged on postoperative day 4 without any complications. LESSONS: Developing a treatment plan in cases of multiple sharp FB may be difficult. A multidisciplinary team of endoscopists and surgeons is needed to determine the best possible treatment plan. This experience illustrates the importance of the planning of the sequence and method of removal of multiple foreign bodies from the gastrointestinal tract.

Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma.

The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70-75 mg/m(2)) and cisplatin (70-75 mg/m(2)) on day 1, and continuous infusion of fluorouracil (750 mg/m(2)/day) on days 1-5. Antibiotic prophylaxis on days 5-15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty-two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty-one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment-related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2-year progression-free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).

[A case of recurrent rectal cancer with paraaortic lymph node metastasis treated by FOLFIRI therapy leading to complete response].

A 56-year-old woman was referred to our hospital because of melena. After examinations she was diagnosed with rectal cancer. Anterior resection was performed and the final diagnosis was Stage IIIa. She was treated with adjuvant chemotherapy consisting of UFT/Uzel for one year, followed by UFT alone for one year. Two years after the surgery, abdominal CT suggested solitary paraaortic lymph node metastasis. As the patient denied a surgical treatment, mFOLFOX6 chemotherapy was induced. However, the patient developed a grade 3 allergic side effect, FOLFIRI was administered. Six months after the chemotherapy was started, the paraaortic lymph node metastasis had disappeared. After 50 courses, the case was considered to have achieved a clinical CR which has been maintained now. FOLFIRI was effective for recurrent rectal cancer with paraaortic LN metastasis.

Efficacy and Safety of a Traditional Herbal Medicine, Hochu-ekki-to in the Long-term Management of Kikyo (Delicate Constitution) Patients with Atopic Dermatitis: A 6-month, Multicenter, Double-blind, Randomized, Placebo-controlled Study.

Hochu-ekki-to is a traditional herbal (Kampo) medicine that has been shown to be effective for patients with Kikyo (delicate, easily fatigable, or hypersensitive) constitution. Previous case reports have suggested that this herbal drug was effective for a certain subgroup of patients with atopic dermatitis (AD). We aimed to evaluate the efficacy and safety of Hochu-ekki-to in the long-term management of Kikyo patients with AD. In this multicenter, double blind, randomized, placebo-controlled study, 91 Kikyo patients with AD were enrolled. Kikyo condition was evaluated by a questionnaire scoring system. All patients continued their ordinary treatments (topical steroids, topical tacrolimus, emollients or oral antihistamines) before and after their protocol entry. Hochu-ekki-to or placebo was orally administered twice daily for 24 weeks. The skin severity scores, total equivalent amount (TEA) of topical agents used for AD treatment, prominent efficacy (cases with skin severity score = 0 at the end of the study) rate and aggravated rate (more than 50% increase of TEA of topical agents from the beginning of the study) were monitored and evaluated. Seventy-seven out of 91 enrolled patients completed the 24-week treatment course (Hochu-ekki-to: n = 37, placebo: n = 40). The TEA of topical agents (steroids and/or tacrolimus) was significantly (P < 0.05) lower in the Hochu-ekki-to group than in the placebo group, although the overall skin severity scores were not statistically different. The prominent efficacy rate was 19% (7 of 37) in the Hochu-ekki-to group and 5% (2 of 40) in the placebo group (P = 0.06). The aggravated rate was significantly (P < 0.05) lower in the Hochu-ekki-to group (3%; 1 of 37) than in the placebo group (18%; 7 of 39). Only mild adverse events such as nausea and diarrhea were noted in both groups without statistical difference. This placebo-controlled study demonstrates that Hochu-ekki-to is a useful adjunct to conventional treatments for AD patients with Kikyo constitution. Use of Hochu-ekki-to significantly reduces the dose of topical steroids and/or tacrolimus used for AD treatment without aggravating AD.

Predictors of tumor downsizing and regression with preoperative radiotherapy alone and with concomitant tegafur/uracil (UFT) for resectable advanced rectal adenocarcinoma.

BACKGROUND/AIMS: Predictors of sensitivity to preoperative radiotherapy (RT) may differ from those of chemo-radiotherapy (CRT). This study attempts to evaluate retrospectively the significance of apoptosis-related and proliferative indexes in biopsy specimens obtained before treatment as predictors of sensitivity to RT or to CRT for locally advanced rectal adenocarcinoma. METHODOLOGY: The subjects were 96 patients with clinical T3-4/Nx/M0 adenocarcinoma of the middle third or lower third of the rectum. Sixty-one patients were treated with preoperative RT alone (20 Gy in 10 fractions) [RT group] during 1991-1998, and 35 patients received concurrent oral tegafur/uracil (UFT) [CRT group] since 1999. Radical surgery including TME and pelvic nerve preservation with 15 Gy of intraoperative RT was performed two weeks after completion of the preoperative radiation. We evaluated apoptotic index (AI) and p53, p21 and Ki-67 protein expression in the biopsy specimens, and histological differentiation, pathologic regression in the resected specimens and the degree of tumor shrinkage based on the double contrast barium enema images. RESULTS: AI-positivity, p53-negativity, p21-positivity and well differentiated adenocarcinoma were predictors of high sensitivity in RT group, whereas AI-positivity alone was the predictor in CRT group. The addition of UFT to RT increased sensitivity in patients with p53-positivity, p21-negativity and moderately differentiated adenocarcinoma. CONCLUSIONS: Predictors of sensitivity are different between RT and CRT.

Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model.

BACKGROUND: Hepatic intra-arterial infusion chemotherapy of 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUDR) has been a treatment option for liver metastasis from colorectal cancer. However, an optimal administration schedule of 5-FU is still controversial. This study was conducted to evaluate a suitable schedule from the viewpoint of 5-FU metabolites and related enzymes. METHODS: 5-FU was infused into the hepatic artery of rabbits having hepatic deposits of VX2 tumor cells in a daily dose of 1, 4, or 8 mg/kg using various schedules. 5-FU, Thymidylate synthase (TS), TS inhibition rate (TSIR), and the amount of fluoro-RNA (F-RNA) were measured. RESULTS: A high concentration of 5-FU was detected in the tumors of the group that was administered a dose of 8 mg/kg. TSIR in the tumor was about two-fold higher in the rabbits that were administered a total dose of 8 mg/kg than in those that were administered doses of 4 mg/kg or less. F-RNA, ranging from 27 to 36 ng/mg RNA, was detected in the tumor of the rabbits that were administered a total dose of 8 mg/kg. No difference was observed between the short period and the continuous administration schedules of rabbits that were administered a dose of 8 mg/kg of 5-FU. However, DNA synthesis inhibition in normal hepatic tissue was more dependent on the administration schedule than on the total dose of 5-FU because TSIR was significantly higher with shorter periods of drug administration. CONCLUSION: Intermittent bolus administration of large doses of 5-FU might cause more severe hepatic impairment than continuous administration. These results suggest that hepatic intra-arterial infusion of 5-FU should be administered continuously for liver metastasis, although further experiments including a longer administration period of 5-FU are required.

Expression of thymidylate synthase and thymidine phosphorylase in recurrence and survival rates of advanced gastric cancer.

BACKGROUND: The immunohistochemical expression of thymidylate synthase (TS) and thymidine phosphorylase (TP) was examined in a comparative study of the recurrence rates and prognoses of patients with advanced gastric cancer at the same stage.METHODS: We examined the resected specimens of 67 patients with stage IIIB gastric cancer (pT3, pN2, M0) under 70 years of age who had undergone curative gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines. Paraffin sections of the resected specimens were stained with human anti-TS polyclonal and anti-TP monoclonal antibodies by the avidin-biotin-peroxidase complex (ABC) method.RESULTS: The overall expression of TS and TP was 45.4% and 43.4%, respectively. The postoperative survival curve for the TS-positive group was significantly depressed compared with that for the TS-negative group ( P = 0.0480). The survival curves for TP-positive and TP-negative groups did not show any difference. In regard to the combination of TS and TP expression, the best survival curve was obtained for the TS(-)/TP(+) group, followed by those for the TS(-)/TP(-), TS(+)/TP(-), and TS(+)/TP(+) groups in descending order. With regard to the recurrence site, there was no significant difference in peritoneal recurrence in relation to positivity for TS or TP. Lymph node recurrence, however, was significantly higher in the TS-positive and TP-positive groups, with P-values being 0.0466 and 0.0058, respectively, versus the corresponding negative groups. The incidence of hepatic recurrence was higher in the TP-positive group than in the TP-negative group ( P = 0.0910). As for the total doses of 5-fluoropyrimidines given, more favorable survival curves were obtained for the high dose of negative TS and TP groups, but no significant differences were observed in their positivities.CONCLUSION: The expressions of TS and TP showed different characteristics in overall survival and recurrence rate or site. They should be used for predicting prognosis in comprehension on their properties.